The most common adult-onset neurodegenerative motor neuron disease is Parkinson's disease (PD). Evidence supports the idea that disruption of axonal transport may cause or contribute to neurodegeneration. PD is a devastating condition that affects more than a million people in the USA alone. Current treatments ameliorate symptoms, but fail to have an effect on progression of the disease or its outcome. It is not known what causes PD, but preliminary observations indicate that pathogenic forms of alpha(a)-synuclein (mutant forms or wild type forms in Lewy body (LB) filaments) alter fast axonal transport by activating retrograde transport (RT) and reducing anterograde transport (AT). Misregulation or compromises in axonal transport have been implicated in pathogenesis of Alzheimer's and Huntington's diseases as well as motor neuron diseases such as Hereditary Spastic Paraplegia and peripheral neuropathies. We propose that the presence of mutant a-synuclein or LB disrupts proper transport in axons and thus compromises neuronal function. Disruption of fast axonal transport can be expected to result in loss of synaptic function and eventually in a loss of neurons. Our experimental aims propose to: 1) determine the role of altered kinase activity in modulating transport in cellular models of synucleinopathy. Experiments will combine pharmacological, immunochemical and molecular biological approaches to establish whether specific kinases play a role in phosphorylating the motor proteins kinesin and dynein. 2) determine molecular motifs within a-synuclein that affect kinases and axonal transport. Site directed mutagenesis of wild type and mutant a-synuclein will be carried out to identify residues and motifs critical to modulating transport. The goal is to identify potential therapeutic targets that may prevent progression of neurodegeneration in PD and protect neurons from the pathogenic consequences of mutant a-synuclein or LB. Relevance: PD is a devastating condition that has no effective treatment. Starting in middle age, patients begin neuronal degeneration that continues until death. My goal is to test possible mechanisms underlying neuronal death in PD, and to find potential therapeutic targets for this disease.